Method of preparation of 4-isopropylamino-1-butanol

ABSTRACT

The present invention relates to a preparation method of 4-isopropylamino-1-butanol, in which using cheap and readily available tetrahydrofuran and acetic acid solution of hydrogen bromide as starting materials to prepare a novel intermediate of 4-isopropylamino-1-acetoxyl butane and further obtain the target product. The present invention has advantages of convenient process operations, mild reaction conditions, economical and environment-friendly benefits, and suitability for industrial production to obtain the product with high purity and high yield.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention is a divisional application of U.S. applicationSer. No. 15/552,772, filed Aug. 22, 2017, which is a U.S. national phaseof International Application No. PCT/CN2016/000180 under 35 U.S.C. §371. The teaching in these related applications are incorporated hereinin its entirety by reference.

FIELD OF THE INVENTION

The present invention relates to the technical field of chemicalsynthesis in pharmaceutical industry, specifically, it relates to apreparation method of 4-isopropylamino-1-butanol and a novelintermediate thereof.

BACKGROUND

4-isopropylamino-1-butanol is an important intermediate inpharmaceutical industry, and its structural formula is represented byformula (I):

4-isopropylamino-1-butanol was widely used in the pharmaceuticalsynthesis, for example, Patent Document WO2002088084A1 disclosed afour-step reaction using 4-isopropylamino-1-butanol as the raw materialto prepare pulmonary hypertension drug of selexipag. This document wasincorporated by reference into the present application.

Journal of Organic Chemistry (1961), Vol. 26, P 1744-1747 disclosed apreparation method of 4-isopropylamino-1-butanol, which comprised: (1)reacted succinic anhydride with isopropyl amine to obtain 3-isopropylcarbamoyl propionic acid; (2) reduced 3-isopropylcarbamoyl propionicacid with lithium aluminum hydride to obtain 4-isopropylamino-1-butanol.

This method had defects: lithium aluminum hydride was expensive, largeconsumed and high cost; lithium aluminum hydride was also a strongreducing agent with great security risks, when it meets water, explosionmay be happened, so there were strict requirements for the watercontents of the solvents; the yield was low; a large amount of wastewater containing aluminum was produced, post-treatment was complicated,and this method was unsuitable for industrial production.

Organic and Biomolecular Chemistry (2012), Vol. 10, P 6504-6511disclosed a preparation method of 4-isopropylamino-1-butanol, whichcomprised: a reduction reaction was carried out between DIBAL-H.i-PrNH2and γ-butyrolactone in a hexane solution of diisobutylaluminium hydride(DIBAL-H) to obtain 4-isopropylamino-1-butanol. The reaction formula wasshown below:

This method had defects: DIBAL-H.i-PrNH2 was needed to be preparedfreshly; DIBAL-H was expensive and unstable so only its hexane solutioncould be used; column chromatography was used in the post-treatment; alarge amount of waste water containing aluminum was produced, and thismethod was unsuitable for industrial production.

European Patent Document EP1400518A1 disclosed a synthesis method for4-isopropylamino-1-butanol, which comprised: reacted 4-aminobutanol withacetone in ethanol, then kept a hydrogenation reaction at 2-3atmospheres for 48 hours under catalyzing of platinum oxide to obtain4-isopropylamino-1-butanol. The reaction formula was shown below:

In this process, 4-aminobutanol and platinum oxide were expensive,special high-pressure hydrogenation equipment was needed, so itsindustrial application was limited.

Therefore, there still had some defects in the known preparation methodsof 4-isopropylamino-1-butanol in the conventional methods, it wasnecessary to develop novel preparation methods thereof.

SUMMARY OF THE INVENTION

The objective of the present invention is to provide a novel synthesisroute of 4-isopropylamino-1-butanol represented by formula (I), whichwill benefit for process feasibility, safety and environmentalprotection, obtaining a product with low cost and high quality, andsuitability for industrial production.

According to the objective of the present invention, a preparationmethod of 4-isopropylamino-1-butanol represented by formula (I) isprovided, which comprising the following steps:

(1) reacting tetrahydrofuran with an acetic acid solution of hydrogenbromide to obtain 4-bromo-1-acetoxyl butane represented by formula(III);

(2) reacting 4-bromo-1-acetoxyl butane represented by formula (III) withisopropyl amine to obtain 4-isopropylamino-1-acetoxyl butane representedby formula (II); and

(3) hydrolyzing 4-isopropylamino-1-acetoxyl butane represented byformula (II) to obtain 4-isopropylamino-1-butanol represented by formula(I).

In the step (1), the mass content of hydrogen bromide in the acetic acidsolution of hydrogen bromide is 10% to 40%; preferably, 33% or 40%,because such kind of solution is readily available commercially.

In the step (1), the molar ratio of tetrahydrofuran to hydrogen bromideis 1:1 to 50:1; preferably, 2:1 to 15:1; more preferably, 2:1 to 5:1.

In the step (1), the reaction temperature is 0 to 50° C.; preferably, 10to 25° C.

After completion of the step (1), 4-bromo-1-acetoxyl butane (III) wascollected by vacuum distillation, and the excess tetrahydrofuran andacetic acid were recovered.

In the step (1), the process is feasible with low cost and simpleoperations, the yield of 4-bromo-1-acetoxyl butane (III) is high and itsgas chromatographic purity is up to 99.5%.

In the step (2), the molar ratio of isopropyl amine to4-bromo-1-acetoxyl butane (III) is 1:1 to 10:1; preferably, 2:1 to 5:1.

The step (2) reaction can be carried out in the presence of an alkali soas to accelerate the reaction rate, moderate the reaction conditions,simplify the post-treatment and improve the yield. The alkali isselected from the group consisting of carbonates, bicarbonates,phosphates, hydrophosphates and organic amines; preferably, the alkaliis selected from the group consisting of sodium carbonate, potassiumcarbonate, sodium bicarbonate, sodium phosphate, potassium phosphate,potassium hydrophosphate, triethylamine, pyridine, diisopropylethylamineand isopropylamine.

The reaction solvent of the step (2) is selected from the groupconsisting of chlorinated alkanes, alcohols, strong polar aproticsolvents and non-polar aprotic solvents; preferably, the reactionsolvent of the step (2) is selected from the group consisting ofdichloromethane, acetonitrile, ethanol, ethyl acetate and N,N-dimethylformamide.

The reaction temperature of the step (2) is 0 to 50° C.; preferably, 0to 30° C.

After completion of the step (2), 4-isopropylamino-1-acetoxyl butane(II) can be collected by filtration, concentration or extraction,further be purified by recrystallization.

In the step (3), the hydrolyzing reaction can be carried out in thepresence of an acid. The acid, for example, is sulfuric acid orp-toluenesulfonic acid.

Preferably, the hydrolyzing reaction of the step (3) is carried out inthe presence of an alkali, which will benefit for acceleration ofreaction rate, improvement of reaction selectivity, simplification ofthe post-treatment and producing a product with high purity and highyield. The alkali is selected from the group consisting of sodiumhydroxide, potassium hydroxide and lithium hydroxide. The molar ratio of4-isopropylamino-1-acetoxyl butane to the alkali is 1:1 to 1:5,preferably, 1:1 to 1:2.

In the step (3), the solvent of the hydrolyzing reaction is selectedfrom the group consisting of water, C1-4 alcohols and the mixturesthereof; preferably, the solvent of the hydrolyzing reaction is selectedfrom the group consisting of methanol, ethanol and water.

In the step (3), the temperature of the hydrolyzing reaction is −20 to80° C.; preferably, 0 to 30° C.

After completion of the step (3), the product can be separated andpurified by normal methods in the field, for example, filtration,concentration, extraction or distillation.

The product, 4-isopropylamino-1-butanol, has high yield and its gaschromatographic purity is up to ≥99.5%, which will satisfy therequirements for high quality intermediates in the pharmaceuticalindustry so as to benefit for the subsequent synthesis reactions andobtain drugs with high quality and high yield. Especially, for themulti-step synthesis of pulmonary hypertension drug of selexipag, it isneeded to use 4-isopropylamino-1-butanol with high quality and highyield prepared by the present invention.

In addition, the present invention provides a novel intermediate of4-isopropylamino-1-acetoxyl butane represented by formula (II). It is akey intermediate in the preparation of 4-isopropylamino-1-butanol (I).

Compared with conventional methods, the present invention provides anovel preparation method of 4-isopropylamino-1-butanol, in which usingcheap and readily available tetrahydrofuran and acetic acid solution ofhydrogen bromide as starting materials to prepare a novel intermediateof 4-isopropylamino-1-acetoxyl butane and further obtain4-isopropylamino-1-butanol. This feasible synthesis route has simpleoperations, mild reaction conditions and low cost, it is environmentallyfriendly, and no special equipment is needed. The product with highpurity and high yield is suitable for being used in the drug synthesisand industrial production.

EXAMPLES

The following examples describe the preparation method of the presentinvention in details. Those examples will help to further understand thepresent invention, but not be used to restrict the scope of the presentinvention.

Raw materials and reagents used in the examples are commerciallyavailable.

Analysis methods in the present invention:

Gas chromatography (GC) detection uses Agilent 7890A Gas Chromatograph.

Proton nuclear magnetic resonance spectras (1H-NMR) are recorded on a400 MHz FT-NMR spectrometer, Bruker Avance 400, Bruker Corporation.

Example 1: Preparation of 4-bromo-1-acetoxyl butane

185 mL of tetrahydrofuran was added to a 500 mL four-neck flask andcooled to 10° C. by ice-water bath, 280 g acetic acid solution ofhydrogen bromide with its mass content of 33% was added dropwise, thenthe mixture was heated to 25° C. and reacted at this temperature for 2hours until the reaction was completed.

Tetrahydrofuran and acetic acid were recovered by vacuum distillation,the residue was heated to 100° C. and distilled at 2 mmHg vacuum, then87 to 89° C. component fraction was collected to obtain 200 g ofcolorless clear liquid of 4-bromo-1-acetoxyl butane. The molar yield:90%, GC purity: 99.5%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.05 (t, J=6.4 Hz, 2H), 3.39 (t, J=6.8Hz, 2H), 1.99 (s, 3H), 1.86 (m, 2H), 1.75 (m, 2H).

Example 2: Preparation of 4-bromo-1-acetoxyl butane

460 mL of tetrahydrofuran was added to a 1000 mL four-neck flask andcooled to 10° C. by ice-water bath, 280 g acetic acid solution ofhydrogen bromide with its mass content of 33% was added dropwise, thenthe mixture was kept at 10° C. for 4 hours to react until the reactionwas completed.

Tetrahydrofuran and acetic acid were recovered by vacuum distillation,the residue was heated to 100° C. and distilled at 2 mmHg vacuum, then87 to 89° C. component fraction was collected to obtain 206 g ofcolorless clear liquid of 4-bromo-1-acetoxyl butane. The molar yield:93%, GC purity: 99.5%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.05 (t, J=6.4 Hz, 2H), 3.39 (t, J=6.8Hz, 2H), 1.99 (s, 3H), 1.86 (m, 2H), 1.75 (m, 2H).

Example 3: Preparation of 4-bromo-1-acetoxyl butane

93 mL of tetrahydrofuran was added to a 1000 mL four-neck flask andcooled to 10° C. by ice-water bath, 230 g acetic acid solution ofhydrogen bromide with its mass content of 40% was added dropwise, thenthe mixture was kept at 10° C. for 3 hours to react until the reactionwas completed.

Tetrahydrofuran and acetic acid were recovered by vacuum distillation,the residue was heated to 100° C. and distilled at 2 mmHg vacuum, then87 to 89° C. component fraction was collected to obtain 184 g ofcolorless clear liquid of 4-bromo-1-acetoxyl butane. The molar yield:83%, GC purity: 99.5%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.05 (t, J=6.4 Hz, 2H), 3.39 (t, J=6.8Hz, 2H), 1.99 (s, 3H), 1.86 (m, 2H), 1.75 (m, 2H).

Example 4: Preparation of 4-bromo-1-acetoxyl butane

185 mL of tetrahydrofuran was added to a 2000 mL four-neck flask andcooled to 20° C. by ice-water bath, 920 g acetic acid solution ofhydrogen bromide with its mass content of 10% was added dropwise, thenthe mixture was heated to 50° C. and reacted for 3 hours until thereaction was completed.

Tetrahydrofuran and acetic acid were recovered by vacuum distillation,the residue was heated to 100° C. and distilled at 2 mmHg vacuum, then87 to 89° C. component fraction was collected to obtain 194 g ofcolorless clear liquid of 4-bromo-1-acetoxyl butane. The molar yield:87%, GC purity: 99.5%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.05 (t, J=6.4 Hz, 2H), 3.39 (t, J=6.8Hz, 2H), 1.99 (s, 3H), 1.86 (m, 2H), 1.75 (m, 2H).

Example 5: Preparation of 4-isopropylamino-1-acetoxyl butane

39 g of 4-bromo-1-acetoxyl butane, 250 mL of acetonitrile and 100 g ofsodium bicarbonate were added to a 500 mL four-neck flask and cooled to5° C. by ice-water bath, 35.4 g of isopropyl amine was added dropwise,then the mixture was heated to 20° C. and reacted for 5 hours until thereaction was completed.

Inorganic salts were removed by filtration, the filtrate wasconcentrated to recover acetonitrile, 300 mL of ethyl acetate was addedto the residue to recrystallize, and 31.8 g of4-isopropylamino-1-acetoxyl butane was obtained. The molar yield was92%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.02 (t, J=6.8 Hz, 2H), 2.74 (m, 1H),2.57 (t, J=7.2 Hz, 2H), 1.97 (s, 3H), 1.62 (m, 2H), 1.49 (m, 2H), 0.99(d, J=6.0 Hz, 6H).

Example 6: Preparation of 4-isopropylamino-1-acetoxyl butane

39 g of 4-bromo-1-acetoxyl butane, 250 mL of acetonitrile and 100 g ofsodium bicarbonate were added to a 500 mL four-neck flask, 11.5 g ofisopropyl amine was added dropwise, then the mixture was heated to 50°C. and reacted for 2 hours until the reaction was completed.

Inorganic salts were removed by filtration, the filtrate wasconcentrated to recover acetonitrile, 300 mL of ethyl acetate was addedto the residue to recrystallize, and 28.7 g of4-isopropylamino-1-acetoxyl butane was obtained. The molar yield was83%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.02 (t, J=6.8 Hz, 2H), 2.74 (m, 1H),2.57 (t, J=7.2Hz, 2H), 1.97 (s, 3H), 1.62 (m, 2H), 1.49 (m, 2H), 0.99(d, J=6.0 Hz, 6H).

Example 7: Preparation of 4-isopropylamino-1-acetoxyl butane

39 g of 4-bromo-1-acetoxyl butane, 200 mL of dichloromethane and 25 g oftriethylamine were added to a 500 mL four-neck flask and cooled to 10°C., 23 g of isopropyl amine was added dropwise, then the mixture waskept at this temperature for 2 hours to react until the reaction wascompleted.

50 mL of water was added to wash, the organic phase was concentrated torecover dichloromethane, 200 mL of ethyl acetate was added to theresidue to recrystallize, and 30.5 g of 4-isopropylamino-1-acetoxylbutane was obtained. The molar yield was 83%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.02 (t, J=6.8 Hz, 2H), 2.74 (m, 1H),2.57 (t, J=7.2 Hz, 2H), 1.97 (s, 3H), 1.62 (m, 2H), 1.49 (m, 2H), 0.99(d, J=6.0 Hz, 6H).

Example 8: Preparation of 4-isopropylamino-1-acetoxyl butane

39 g of 4-bromo-1-acetoxyl butane and 250 mL of ethyl acetate were addedto a 500 mL four-neck flask, 115 g of isopropyl amine was addeddropwise, then the mixture was heated to 20° C. and reacted for 5 hoursuntil the reaction was completed.

50 mL of water was added, the mixture was stirred for 10 minutes,filtered and dried to obtain 30 g of 4-isopropylamino-1-acetoxyl butane.The molar yield was 87%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.02 (t, J=6.8 Hz, 2H), 2.74 (m, 1H),2.57 (t, J=7.2 Hz, 2H), 1.97 (s, 3H), 1.62 (m, 2H), 1.49 (m, 2H), 0.99(d, J=6.0 Hz, 6H).

Example 9: Preparation of 4-isopropylamino-1-acetoxyl butane

39 g of 4-bromo-1-acetoxyl butane, 250 mL of acetonitrile and 100 g ofsodium bicarbonate were added to a 500 mL four-neck flask, 57.5 g ofisopropyl amine was added dropwise, then the mixture was heated to 30°C. and reacted for 5 hours until the reaction was completed.

Inorganic salts were removed by filtration, the filtrate wasconcentrated to recover acetonitrile, 300 mL of ethyl acetate was addedto the residue to recrystallize, and 29.4 g of4-isopropylamino-1-acetoxyl butane was obtained. The molar yield was88%.

¹H-NMR data: (400 MHz, CDCl3) δ: 4.02 (t, J=6.8 Hz, 2H), 2.74 (m, 1H),2.57 (t, J=7.2 Hz, 2H), 1.97 (s, 3H), 1.62 (m, 2H), 1.49 (m, 2H), 0.99(d, J=6.0 Hz, 6H).

Example 10: Preparation of 4-isopropylamino-1-butanol

34 g of 4-isopropylamino-1-acetoxyl butane and 200 mL of ethanol wereadded to a 250 mL three-neck flask, a solution containing 8 g of sodiumhydroxide dissolved in 20 mL of water was added dropwise while thetemperature was maintained 10° C., then the mixture was stirred at 20°C. for 2 hours to react until the reaction was completed.

Ethanol was recovered by concentration, 200 mL of dichloromethane and100 mL of water were added to the residue to extract, the organic phasewas dried by sodium sulfate and dichloromethane was recovered byconcentration, then the residue was distilled at 1 mmHg vacuum and 83 to85° C. component fraction was collected to obtain 24.7 g of4-isopropylamino-1-butanol (this product will be solidified in theenvironment of the temperature below 10° C.). The molar yield: 95%, GCpurity: 99.5%.

¹H-NMR data: (400 MHz, CDCl3) δ: 3.51 (t, J=5.2 Hz, 2H), 2.76 (m, 1H),2.58 (t, J=5.6 Hz, 2H), 1.62 (m, 2H), 1.55 (m, 2H), 1.02 (d, J=6.4 Hz,6H).

Example 11: Preparation of 4-isopropylamino-1-butanol

34 g of 4-isopropylamino-1-acetoxyl butane and 200 mL of ethanol wereadded to a 250 mL three-neck flask, a solution containing 16 g of sodiumhydroxide dissolved in 20 mL of water was added dropwise while thetemperature was maintained 0° C., then the mixture was stirred at 30° C.for 1 hour to react until the reaction was completed.

Ethanol was recovered by concentration, 200 mL of dichloromethane and100 mL of water were added to the residue to extract, the organic phasewas dried by sodium sulfate and dichloromethane was recovered byconcentration, then the residue was distilled at 1 mmHg vacuum and 83 to85° C. component fraction was collected to obtain 22.6 g of4-isopropylamino-1-butanol. The molar yield: 87%, GC purity: 99.5%.

¹H-NMR data: (400 MHz, CDCl3) δ: 3.51 (t, J=5.2 Hz, 2H), 2.76 (m, 1H),2.58 (t, J=5.6 Hz, 2H), 1.62 (m, 2H), 1.55 (m, 2H), 1.02 (d, J=6.4 Hz,6H).

Example 12: Preparation of 4-isopropylamino-1-butanol

34 g of 4-isopropylamino-1-acetoxyl butane and 200 mL of ethanol wereadded to a 250 mL three-neck flask, a solution containing 40 g of sodiumhydroxide dissolved in 50 mL of water was added dropwise while thetemperature was maintained −20° C., then the mixture was stirred at 10°C. for 1 hour to react until the reaction was completed.

Ethanol was recovered by concentration, 200 mL of dichloromethane and100 mL of water were added to the residue to extract, the organic phasewas dried by sodium sulfate and dichloromethane was recovered byconcentration, then the residue was distilled at 1 mmHg vacuum and 83 to85° C. component fraction was collected to obtain 22.1 g of4-isopropylamino-1-butanol. The molar yield: 85%, GC purity: 99.7%.

¹H-NMR data: (400 MHz, CDCl3) δ: 3.51 (t, J=5.2 Hz, 2H), 2.76 (m, 1H),2.58 (t, J=5.6 Hz, 2H), 1.62 (m, 2H), 1.55 (m, 2H), 1.02 (d, J=6.4 Hz,6H).

What is claimed is:
 1. 4-isopropylamino-1-acetoxyl butane represented byformula (II):